Advances in synthetic chemistry have led to the industrial use of tens of thousands of novel compounds to which organisms have not been exposed in all of evolutionary history. Interestingly, the exponential increase in production of these synthetic chemicals is mirrored by a coordinate rise in obesity and diabetes rates in humans. Furthermore, an expanding body of epidemiological studies has linked environmental endocrine disruptors (EDCs) with disturbances in energy homeostasis, but the molecular mechanisms by which EDCs exert their cellular effects remain poorly understood. The proposed studies will test the hypothesis that EDCs that differentially modulate adipocyte function interact with common metabolic stressors to alter glucose homeostasis and the capacity for weight loss. Furthermore, the experimental plan will interrogate the supposition that the metabolic effects of EDCs can be programmed in utero and unmasked in later life. Two mechanistically distinct EDCs will be studied: the novel glucocorticoid receptor (GR) agonist tolylfluanid (TF) and the peroxisome proliferator activated receptor-? (PPAR??) agonist tributyltin (TBT). Since both receptors promote adipogenesis yet can differentially affect insulin action, these studies will ascertain whether EDCs with distinct mechanisms generate opposing metabolic phenotypes. In the first Specific Aim, the effects of these EDCs on global energy metabolism will be comprehensively analyzed under standard feeding conditions as well as during the coordinate metabolic stress of a high fat diet. The ability of these EDCs to antagonize weight loss will also be analyzed in exposed adult mice. In the second Specific Aim, the capacity of each EDC to promote gestational diabetes will be assessed. In conjunction with these experiments, the differential metabolic consequences of in utero exposure to insulin-modulating EDCs will be evaluated using a subsequent weight gain/loss protocol during adulthood. These approaches will analyze the impact of EDC exposure during periods of developmental plasticity on the establishment of metabolic set points to determine whether EDC exposure augments high fat diet-induced insulin resistance while antagonizing weight loss. Importantly, these studies will lin EDC-mediated alterations in global energy homeostasis with specific disruptions in cellular insulin action. The present study will not only characterize the global metabolic consequences of exposure to an entirely novel class of EDCs (TF), but it will also add significant new information about the environmental obesogen TBT, as to our knowledge no reports have investigated its effects on glucose homeostasis during pregnancy, its interaction with obesogenic diets, and its ability to impair weight loss. We will also investigate molecular and metabolic changes at the cellular level of the adipocyte to understand the mechanisms by which these structurally distinct EDCs alter global energy homeostasis. Understanding how these EDCs differentially modulate energy homeostasis under various metabolic stresses will add significantly to our understanding of the impact of environmental pollutants on the risk of metabolic diseases such as obesity and diabetes.